Objectives To investigate the effects of β2-adrenergic antagonist on cytosolic Ca^2 + ([Ca^2+ ]i) in ventricular myocytes from infarcted rat heart. Methods A ligature was placed around left anterior descending co...Objectives To investigate the effects of β2-adrenergic antagonist on cytosolic Ca^2 + ([Ca^2+ ]i) in ventricular myocytes from infarcted rat heart. Methods A ligature was placed around left anterior descending coronary artery of rat hearts. Rats in the control group were sham-operated. Cardiomyocytes were dissociated at two, four, eight weeks after myocardial infarction (MI) and [Ca^2+]i was measured via fura-2 fluorescence. The response of cardiomyocytes to isoproterenol in presence or absence of betal-adrenergic antagonist atenolol, beta2-adrenergic antagonist ICI118, 551 or non-selective β1, 2- adrenergic antagonists propranolol was examined. Results The followings were found that ICI 118, 551 had no significant effects on the rise of [Ca^2+]i induced by isoproterenol in normal ventricular myocytes (P 〉 0.05), ICI118, 551 only significantly attenuated the rise of [Ca^2+]i induced by isoproterenol at four weeks and eight weeks after MI (24.5%±5.7% vs 57.8% ± 13.2%, P〈 0.01; 12.2%±7.9% vs 44.6%±11.3%, P〈 0.01). Atenolol had suppressive effects only in the control group and the post-MI group of two weeks (P 〈 0.05), and propranolol had suppressive effects in the control and all the three post-MI groups (P 〈 0.01). Conclusions Beta2-adrenergic antagonist ICI118, 551 may exert negative effects on Ca^2+ overload initiated by sympathetic stimulation after MI.展开更多
We studied the activation of β2-adrenergic receptor(β2AR) by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics(MD) simulation. The simulation was done on the assumption that β...We studied the activation of β2-adrenergic receptor(β2AR) by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics(MD) simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions(TMs), in the mo- lecular switches, and in the conserved DRY(Aspartic acid, Arginine and Tyrosine) motif. This study provides detailed information concerning the structure ofβ2AR during activation process.展开更多
Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identif...Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identified.Thus,it is extremely warranted to explore more effective and better-tolerated β2-AR blocker.Currently,we demonstrated that baicalin(BA),a major bioactive component of Scutellaria baicalensis Georgi,could significantly attenuate stress hormones especially epinephrine(Epi)-induced breast cancer cell migration and invasion in vitro.Mechanistically,we identified that β2-AR was a direct target of BA via the drug affinity responsive target stability(DARTS)combined with mass spectrum assay,and BA photoaffinity probe with pull-down assay,which was further confirmed by a couple of biophysical and biochemical assays.Furthermore,we demonstrated that BA could directly bind to the Phe193 and Phe-289 of β2-AR,subsequently inhibit cyclic adenosine monophosphate-protein kinase A-focal adhesion kinase(cAMP-PKA-FAK)pathway,and thus impede epithelial-mesenchymal transition(EMT),thereby hindering the metastatic progression of the chronic stress coupled with syngeneic and xenograft in vivo orthotopic and tail vein mouse model.These findings firstly identify BA as a potential b2-AR inhibitor in the treatment of stress-induced breast cancer metastasis.展开更多
Objective: To investigate the effects of gene transfer of a β-adrenergic receptor(β-AR) kinase inhibitor(β ARIct) on pulmonary β2-adrenergic receptor and cAMP following β2-AR agonist treatment in asthmatic m...Objective: To investigate the effects of gene transfer of a β-adrenergic receptor(β-AR) kinase inhibitor(β ARIct) on pulmonary β2-adrenergic receptor and cAMP following β2-AR agonist treatment in asthmatic mice, and to analyze the relationship between the routes of gene delivery and the changes of β2AR and cAMP. Methods: BALB/c mice were sensitized and challenged by ovalbumin to establish the asthmatic model treated with βAR agonist (salbutamol injected intramuscularly). The plasmid with the expression of βARKct was constructed and βARKct gene transfer was performed through intravenous injection or intratracheal instillation in asthmatic mice. The gene expression was measured with Western blot analysis, and the changes of pulmonary β-AR and cAMP evaluated by Radioimmunoassay. Results: The expression of tranfered βARKct gene was detectable in lungs and it was expressed more in the lungs of the mice receiving intratracheally plasmid than those receiving intravenously. The levels of βAR and cAMP were upregulated after using plasmid-βARKct to the asthmatic mice treated with βAR agonist. Conclusion: Our results indicated that there were down-regulation of βAR and cAMP in asthmatic mice treated with βAR agonist. Gene transfer of βARKct could inhibit the extent of the down-regulation of βAR and cAMP. The route of gene delivery could also affect the degree of up-regulation of βAR and cAMP. Gene transfer βARKct may provide a novel approach to the therapeutic strategy for asthma.展开更多
Objective: To scan single nucleotide polymorphism ( SNP ) in Chinese alpha-2Aadrenergic receptor (α_(2A)-AR) gene and study the effects of the SNP on the gene expression.Methods: The complete sequence of α_(2A)-AR g...Objective: To scan single nucleotide polymorphism ( SNP ) in Chinese alpha-2Aadrenergic receptor (α_(2A)-AR) gene and study the effects of the SNP on the gene expression.Methods: The complete sequence of α_(2A)-AR gene was analyzed with automated DNA sequencer to scanSNPs. Genomic DNA was extracted from whole blood and a 239 bp fragment containing the G/Cpolymorphism was amplified with PCR using a pair of. specific primers. PCR-RFLP was used to performthe genotyping of the SNP at the site-1 296 bp of the people in the North of China. Electrophoresismobility shift assay ( EMSA ) was used to study the binding of the 390 bp fragments (- 1 414-1 025bp) with G or C at the site-1 296 bp and nuclear extracts . Results: In our study, two SNPs werefound in α_(2A)-AR gene. Allele frequencies of the SNP at the site-1 296 bp were 0.61 and 0.39 forG and C , and the genotype frequencies were 0.34 , 0.54 and 0.13 for GG, GC and CC respectively fromthe people in the North of China. In the EMSA, a specific binding appeared in the complex ofnuclear extracts and DNA with C at-1 296 bp . Conclusion: Two SNPs exist in α_(2A)-AR gene from thepeople in the North of China , and DNA fragment with allele C of the SNP at the site-1 296 bp couldbind with a specific protein, which could influence the gene expression.展开更多
Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Theref...Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity.Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixedeffects model.Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed.Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.展开更多
BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGL...BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.展开更多
Background: The objective of this study was to compare and analyze the variations in clinical indices before and after treatment of type 2 mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) that we...Background: The objective of this study was to compare and analyze the variations in clinical indices before and after treatment of type 2 mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) that were treated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). Methods: The electronic medical record system was utilized to search for a total of 16 patients with type 2 diabetes complicated by NAFLD who were hospitalized at the First Affiliated Hospital of Yangtze University from October 2022 to April 2023 and treated with GLP-1RA for the first time. The clinical indices were compared before and after 12 weeks of treatment with GLP-1RA. Results: The liver-spleen CT ratio (L/S), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in all patients treated with GLP-1RA after 12 weeks were significantly different (P 0.05). The patients were categorized into two groups based on the types of GLP-1RAs. The changes in L/S, TC, TG, and LDL-C in the long-acting group after treatment were statistically significant (P Conclusions: GLP-1RAs can improve liver function, regulate lipid metabolism, and reduce the severity of fatty liver in patients with T2DM complicated by NAFLD, which demonstrates the importance of clinical applications.展开更多
Nonalcoholic fatty liver disease(NAFLD)is a global epidemic,affecting more than half of the people living with type 2 diabetes(T2D).The relationship between NAFLD and T2D is bidirectional and the presence of one perpe...Nonalcoholic fatty liver disease(NAFLD)is a global epidemic,affecting more than half of the people living with type 2 diabetes(T2D).The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other,which significantly increases the hepatic as well as extrahepatic complications.Until recently,there was no approved pharmacological treatment for NAFLD/nonalcoholic steatohepatitits(NASH).However,there is evidence that drugs used for diabetes may have beneficial effects on NAFLD.Insulin sensitizers acting through peroxisome proliferator-activated receptor(PPAR)modulation act on multiple levels of NAFLD pathogenesis.Pioglitazone(PPARγ agonist)and saroglitazar(PPARα/γagonist)are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D,although data on biopsyproven NASH are lacking with the latter.Initial data on elafibanor(PPARα/δ agonist)and Lanifibranor(pan PPAR agonist)are promising.On the other hand,incretin therapies based on glucagon-like peptide-1(GLP-1)receptor agonists(GLP-1RA)and dual-and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties.GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual-and triple-agonists are required.Furthermore,the long-term safety of these therapies in NAFLD needs to be established.Collaborative efforts among healthcare providers such as primary care doctors,hepatologists,and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.展开更多
[Objectives]The paper was to establish an ultra high performance liquid chromatography-quadrupole/linear ion trap complex mass spectrometry for the determination of 10 kinds ofα2-receptor agonists in animal derived f...[Objectives]The paper was to establish an ultra high performance liquid chromatography-quadrupole/linear ion trap complex mass spectrometry for the determination of 10 kinds ofα2-receptor agonists in animal derived food.[Methods]The samples were extracted with sodium carbonate buffer solution and ethyl acetate,and analyzed by mass spectrometry after solid phase extraction and high performance liquid chromatography separation.[Results]Ten kinds ofα2-receptor agonists showed a good linear relationship in the range of 1-100μg/mL,with the average recovery of over 69%and the relative standard deviation less than 8.32%.The detection limit of 10 kinds of α_(2)-receptor agonists was up to 1μg/kg.[Conclusions]The method has good selectivity and strong anti-interference ability,and can meet the requirements of 10 kinds ofα2-receptor agonists residues in animal derived food.展开更多
Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close rel...Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.展开更多
Objective The aims of the present study were to investigate the associations of 46 A〉G, 79 C〉G, 491 C〉T and 659 C〉G genetic variants of the human beta 2-adrenergic receptor (β2-AR), ADRB2, gene with essential h...Objective The aims of the present study were to investigate the associations of 46 A〉G, 79 C〉G, 491 C〉T and 659 C〉G genetic variants of the human beta 2-adrenergic receptor (β2-AR), ADRB2, gene with essential hypertension (EH) in Xinjiang Kazakans population.Methods A gender-matched case-control (271 hypertensive cases and 267 normotensive controls) study was used to investigate the associations of the four variations in the coding region of ADRB2 with EH. The genotypes of the variants were identified by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) methods. Results 46 A〉G, 79 C〉G and 659 C〉G polymorphisms were common in the Kazakan population, but 491 C〉T was a mutation (frequency ofT allele was only 0.003) and only found in EH group. The fxequency distributions of genotypes and alleles for 659 C〉G between the EH and control groups was significantly different (P〈0.05), while those for 46 A〉G and 79 C〉G polymorphisms were not statistically different. Logistic regression analysis suggested that the G allele of 659 C〉G polymorphism was a risk factor for hypertension (minor allele vs common homo; odds ratio, 13.240, 95% CI, 4.052-43.274; P〈0.05). Covariance analysis showed that systolic and diastolic blood pressure levels in GG+CG group of 659 C〉G were significantly higher than those in the CC group, but no significant difference of blood pressure were found between common homo and minor allele for 46 A〉G and 79C〉G polymorphisms. Haplotype analysis showed that two hyplotypes, HI: 46A-79C-491C-523C(48%)and H5:46A-79C-491C-659G, were associated with EH.Conelusion ADRB2 genetic variants may play independent roles in the molecular genetic mechanism of EH in Xinjiang Kazakans population (d Geriatr Cardio12010; 7:52-57).展开更多
Aim:In this study,we would like to determine associations between β2-Adrenergic Receptor(β2AR)polymorphisms at codon 16 and 27 and the response to short acting β2-agonist during asthmatic exacerbation.Methods:This ...Aim:In this study,we would like to determine associations between β2-Adrenergic Receptor(β2AR)polymorphisms at codon 16 and 27 and the response to short acting β2-agonist during asthmatic exacerbation.Methods:This was a prospective cross-sectional study of one year duration.One hundred and thirty two asthmatic patients were recruited.Five mls of venous blood was taken for DNA extraction and then genotyped for the β2AR polymorphisms using multiplex PCR.Patient's clinical responses to β2-agonist nebulization were then compared to their genotype to determine the association.Results:We found that there was no association between β2AR polymorphisms at both codon 16 and 27 with response towards short acting β2-agonist,P=0.315 and P=0.706 respectively.Conclusion:We suggested that β2AR polymorphisms at both codon 16 and 27 had no influent on the response to short acting β2-agonist.展开更多
文摘Objectives To investigate the effects of β2-adrenergic antagonist on cytosolic Ca^2 + ([Ca^2+ ]i) in ventricular myocytes from infarcted rat heart. Methods A ligature was placed around left anterior descending coronary artery of rat hearts. Rats in the control group were sham-operated. Cardiomyocytes were dissociated at two, four, eight weeks after myocardial infarction (MI) and [Ca^2+]i was measured via fura-2 fluorescence. The response of cardiomyocytes to isoproterenol in presence or absence of betal-adrenergic antagonist atenolol, beta2-adrenergic antagonist ICI118, 551 or non-selective β1, 2- adrenergic antagonists propranolol was examined. Results The followings were found that ICI 118, 551 had no significant effects on the rise of [Ca^2+]i induced by isoproterenol in normal ventricular myocytes (P 〉 0.05), ICI118, 551 only significantly attenuated the rise of [Ca^2+]i induced by isoproterenol at four weeks and eight weeks after MI (24.5%±5.7% vs 57.8% ± 13.2%, P〈 0.01; 12.2%±7.9% vs 44.6%±11.3%, P〈 0.01). Atenolol had suppressive effects only in the control group and the post-MI group of two weeks (P 〈 0.05), and propranolol had suppressive effects in the control and all the three post-MI groups (P 〈 0.01). Conclusions Beta2-adrenergic antagonist ICI118, 551 may exert negative effects on Ca^2+ overload initiated by sympathetic stimulation after MI.
基金Supported by the Young and Middle-Aged Scientists Research Awards Foundation of Shangdong Province,China(No.BS2011SW002)the Research Foundation for Advanced Talents of Ludong University,China(No.LY2011017)
文摘We studied the activation of β2-adrenergic receptor(β2AR) by norepinephrine, epinephrine and isoprote- renol using docking and molecular dynamics(MD) simulation. The simulation was done on the assumption that β2AR was surrounded with explicit water and infinite lipid bilayer membrane at body temperature. So the result should be close to that under the physiological conditions. We calculated the structure of binding sites in β2AR for the three ac- tivators. We also simulated the change of the conformation ofβ2AR in the transmembrane regions(TMs), in the mo- lecular switches, and in the conserved DRY(Aspartic acid, Arginine and Tyrosine) motif. This study provides detailed information concerning the structure ofβ2AR during activation process.
基金supported by the Matching Grant of National Natural Science Foundation of China from Nanjing University of Chinese Medicine(Grant Nos.:NZY81903857,and NZY81703765)the National Natural Science Foundation of China(Grant No.:21877062)+1 种基金the Opening Project of Chinese Materia Medica FirstClass Discipline of Nanjing University of Chinese Medicine(Grant No.:2020YLXK020)Postgraduate Research&Practice Innovation Program of Jiangsu Province(Grant Nos.:SJCX21_0707,KYCX21_1772,and KYCX22_2039).
文摘Recent studies have shown that stress can substantially facilitate breast cancer metastasis,which can be reduced by nonselective β1/β2-adrenergic receptor(β1/β2-AR)blocker.However,several side effects were identified.Thus,it is extremely warranted to explore more effective and better-tolerated β2-AR blocker.Currently,we demonstrated that baicalin(BA),a major bioactive component of Scutellaria baicalensis Georgi,could significantly attenuate stress hormones especially epinephrine(Epi)-induced breast cancer cell migration and invasion in vitro.Mechanistically,we identified that β2-AR was a direct target of BA via the drug affinity responsive target stability(DARTS)combined with mass spectrum assay,and BA photoaffinity probe with pull-down assay,which was further confirmed by a couple of biophysical and biochemical assays.Furthermore,we demonstrated that BA could directly bind to the Phe193 and Phe-289 of β2-AR,subsequently inhibit cyclic adenosine monophosphate-protein kinase A-focal adhesion kinase(cAMP-PKA-FAK)pathway,and thus impede epithelial-mesenchymal transition(EMT),thereby hindering the metastatic progression of the chronic stress coupled with syngeneic and xenograft in vivo orthotopic and tail vein mouse model.These findings firstly identify BA as a potential b2-AR inhibitor in the treatment of stress-induced breast cancer metastasis.
文摘Objective: To investigate the effects of gene transfer of a β-adrenergic receptor(β-AR) kinase inhibitor(β ARIct) on pulmonary β2-adrenergic receptor and cAMP following β2-AR agonist treatment in asthmatic mice, and to analyze the relationship between the routes of gene delivery and the changes of β2AR and cAMP. Methods: BALB/c mice were sensitized and challenged by ovalbumin to establish the asthmatic model treated with βAR agonist (salbutamol injected intramuscularly). The plasmid with the expression of βARKct was constructed and βARKct gene transfer was performed through intravenous injection or intratracheal instillation in asthmatic mice. The gene expression was measured with Western blot analysis, and the changes of pulmonary β-AR and cAMP evaluated by Radioimmunoassay. Results: The expression of tranfered βARKct gene was detectable in lungs and it was expressed more in the lungs of the mice receiving intratracheally plasmid than those receiving intravenously. The levels of βAR and cAMP were upregulated after using plasmid-βARKct to the asthmatic mice treated with βAR agonist. Conclusion: Our results indicated that there were down-regulation of βAR and cAMP in asthmatic mice treated with βAR agonist. Gene transfer of βARKct could inhibit the extent of the down-regulation of βAR and cAMP. The route of gene delivery could also affect the degree of up-regulation of βAR and cAMP. Gene transfer βARKct may provide a novel approach to the therapeutic strategy for asthma.
文摘Objective: To scan single nucleotide polymorphism ( SNP ) in Chinese alpha-2Aadrenergic receptor (α_(2A)-AR) gene and study the effects of the SNP on the gene expression.Methods: The complete sequence of α_(2A)-AR gene was analyzed with automated DNA sequencer to scanSNPs. Genomic DNA was extracted from whole blood and a 239 bp fragment containing the G/Cpolymorphism was amplified with PCR using a pair of. specific primers. PCR-RFLP was used to performthe genotyping of the SNP at the site-1 296 bp of the people in the North of China. Electrophoresismobility shift assay ( EMSA ) was used to study the binding of the 390 bp fragments (- 1 414-1 025bp) with G or C at the site-1 296 bp and nuclear extracts . Results: In our study, two SNPs werefound in α_(2A)-AR gene. Allele frequencies of the SNP at the site-1 296 bp were 0.61 and 0.39 forG and C , and the genotype frequencies were 0.34 , 0.54 and 0.13 for GG, GC and CC respectively fromthe people in the North of China. In the EMSA, a specific binding appeared in the complex ofnuclear extracts and DNA with C at-1 296 bp . Conclusion: Two SNPs exist in α_(2A)-AR gene from thepeople in the North of China , and DNA fragment with allele C of the SNP at the site-1 296 bp couldbind with a specific protein, which could influence the gene expression.
基金supported by The Beijing Natural Science Foundation[No.7202216]the National Natural Science Foundation of China[No.81970698 and No.81970708].
文摘Objective Recent studies have indicated potential anti-inflammatory effects of glucagon-like peptide-1 receptor agonists(GLP-1RAs)on asthma,which is often comorbid with type 2 diabetes mellitus(T2DM)and obesity.Therefore,we conducted a meta-analysis to assess the association between the administration of glucagon-like peptide-1(GLP-1)receptor-based agonists and the incidence of asthma in patients with T2DM and/or obesity.Methods PubMed,Web of Science,Embase,the Cochrane Central Register of Controlled Trials,and Clinicaltrial.gov were systematically searched from inception to July 2023.Randomized controlled trials(RCTs)of GLP-1 receptor-based agonists(GLP-1RA,GLP-1 based dual and triple receptor agonist)with reports of asthma events were included.Outcomes were computed as risk ratios(RR)using a fixedeffects model.Results Overall,39 RCTs with a total of 85,755 participants were included.Compared to non-GLP-1 receptor-based agonist users,a trend of reduced risk of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments,although the difference was not statistically significant[RR=0.91,95%confidence interval(CI):0.68 to 1.24].Further Subgroup analyses indicated that the use of light-molecular-weight GLP-1RAs might be associated with a reduced the risk of asthma when compared with non-users(RR=0.65,95%CI:0.43 to 0.99,P=0.043).We also performed sensitivity analyses for participant characteristics,study design,drug structure,duration of action,and drug subtypes.However,no significant associations were observed.Conclusion Compared with non-users,a modest reduction in the incidence of asthma was observed in patients with T2DM or obesity using GLP-1 receptor-based agonist treatments.Further investigations are warranted to assess the association between GLP-1 receptor-based agonists and the risk of asthma.
基金Supported by China Scholarship Council,No.202006920018Key Talent Program for Medical Applications of Nuclear Technology,No.XKTJ-HRC2021007+2 种基金the Second Affiliated Hospital of Soochow University,No.SDFEYBS1815 and No.SDFEYBS2008National Natural Science Foundation of China,No.82170831The Jiangsu Innovation&Career Fund for PhD 2019.
文摘BACKGROUND Glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are associated with significant cardiovascular benefit in type 2 diabetes(T2D).However,GLP-1RA or SGLT-2I alone may not improve some cardiovascular outcomes in patients with prior cardiovascular co-morbidities.AIM To explore whether combining GLP-1RA and SGLT-2I can achieve additional benefit in preventing cardiovascular diseases in T2D.METHODS The systematic review was conducted according to PRISMA recommendations.The protocol was registered on PROSPERO(ID:42022385007).A total of 107049 participants from eligible cardiovascular outcomes trials of GLP-1RA and SGLT-2I were included in network meta-regressions to estimate cardiovascular benefit of the combination treatment.Effect modification of prior myocardial infarction(MI)and heart failure(HF)was also explored to provide clinical insight as to when the INTRODUCTION The macro-and micro-vascular benefits of glucagon-like peptide-1 receptor agonists(GLP-1RA)and sodium-glucose co-transporter-2 inhibitors(SGLT-2I)are independent of their glucose-lowering effects[1].In patients with type 2 diabetes(T2D),the major cardiovascular outcome trials(CVOT)showed that dipeptidyl peptidase-4 inhibitors(DPP-4I)did not improve cardiovascular outcomes[2],whereas cardiovascular benefit of GLP-1RA or SGLT-2I was significant[3,4].Further subgroup analyses indicated that the background cardiovascular risk should be considered when examining the cardiovascular outcomes of these newer glucose-lowering medications.For instance,prevention of major adverse cardiovascular events(MACE)was only seen in those patients with baseline atherosclerotic cardiovascular disease[3,4].Moreover,a series of CVOT conducted in patients with heart failure(HF)have demonstrated that(compared with placebo)SGLT-2I significantly reduced risk of hospitalization for HF or cardiovascular death,irrespective of their history of T2D[5-8].However,similar cardiovascular benefits were not observed in those with myocardial infarction(MI)[9,10].Cardiovascular co-morbidities are not only approximately twice as common but are also associated with dispropor-tionately worse cardiovascular outcomes in patients with T2D,compared to the general population[11].Therefore,it is of clinical importance to investigate whether the combination treatment of GLP-1RA and SGLT-2I could achieve greater cardiovascular benefit,particularly when considering patients with cardiovascular co-morbidities who may not gain sufficient cardiovascular protection from the monotherapies.This systematic review with multiple network meta-regressions was mainly aimed to explore whether combining GLP-1RA and SGLT-2I can provide additional cardiovascular benefit in T2D.Cardiovascular outcomes of these newer antidiabetic medications were also estimated under effect modification of prior cardiovascular diseases.This was to provide clinical insight as to when the combination treatment might be prioritized.
文摘Background: The objective of this study was to compare and analyze the variations in clinical indices before and after treatment of type 2 mellitus (T2DM) combined with nonalcoholic fatty liver disease (NAFLD) that were treated with glucagon-like peptide 1 receptor agonists (GLP-1RAs). Methods: The electronic medical record system was utilized to search for a total of 16 patients with type 2 diabetes complicated by NAFLD who were hospitalized at the First Affiliated Hospital of Yangtze University from October 2022 to April 2023 and treated with GLP-1RA for the first time. The clinical indices were compared before and after 12 weeks of treatment with GLP-1RA. Results: The liver-spleen CT ratio (L/S), alanine aminotransferase (ALT), gamma-glutamyltransferase (GGT), total cholesterol (TC), triglyceride (TG), and low-density lipoprotein cholesterol (LDL-C) in all patients treated with GLP-1RA after 12 weeks were significantly different (P 0.05). The patients were categorized into two groups based on the types of GLP-1RAs. The changes in L/S, TC, TG, and LDL-C in the long-acting group after treatment were statistically significant (P Conclusions: GLP-1RAs can improve liver function, regulate lipid metabolism, and reduce the severity of fatty liver in patients with T2DM complicated by NAFLD, which demonstrates the importance of clinical applications.
文摘Nonalcoholic fatty liver disease(NAFLD)is a global epidemic,affecting more than half of the people living with type 2 diabetes(T2D).The relationship between NAFLD and T2D is bidirectional and the presence of one perpetuates the other,which significantly increases the hepatic as well as extrahepatic complications.Until recently,there was no approved pharmacological treatment for NAFLD/nonalcoholic steatohepatitits(NASH).However,there is evidence that drugs used for diabetes may have beneficial effects on NAFLD.Insulin sensitizers acting through peroxisome proliferator-activated receptor(PPAR)modulation act on multiple levels of NAFLD pathogenesis.Pioglitazone(PPARγ agonist)and saroglitazar(PPARα/γagonist)are particularly beneficial and recommended by several authoritative bodies for treating NAFLD in T2D,although data on biopsyproven NASH are lacking with the latter.Initial data on elafibanor(PPARα/δ agonist)and Lanifibranor(pan PPAR agonist)are promising.On the other hand,incretin therapies based on glucagon-like peptide-1(GLP-1)receptor agonists(GLP-1RA)and dual-and triple-hormone receptor co-agonists reported impressive weight loss and may have anti-inflammatory and antifibrotic properties.GLP-1 RAs have shown beneficial effects on NAFLD/NASH and more studies on potential direct effects on liver function by dual-and triple-agonists are required.Furthermore,the long-term safety of these therapies in NAFLD needs to be established.Collaborative efforts among healthcare providers such as primary care doctors,hepatologists,and endocrinologists are warranted for selecting patients for the best possible management of NAFLD in T2D.
基金Supported by Scientific Research Project of Dalian Customs(2022DK09).
文摘[Objectives]The paper was to establish an ultra high performance liquid chromatography-quadrupole/linear ion trap complex mass spectrometry for the determination of 10 kinds ofα2-receptor agonists in animal derived food.[Methods]The samples were extracted with sodium carbonate buffer solution and ethyl acetate,and analyzed by mass spectrometry after solid phase extraction and high performance liquid chromatography separation.[Results]Ten kinds ofα2-receptor agonists showed a good linear relationship in the range of 1-100μg/mL,with the average recovery of over 69%and the relative standard deviation less than 8.32%.The detection limit of 10 kinds of α_(2)-receptor agonists was up to 1μg/kg.[Conclusions]The method has good selectivity and strong anti-interference ability,and can meet the requirements of 10 kinds ofα2-receptor agonists residues in animal derived food.
基金support from Region Stockholm,ALF-project(FoUI-960041)Open Access funding is provided by Karolinska Institute(both to IM)。
文摘Type 2 diabetes mellitus and Parkinson's disease are chronic diseases linked to a growing pandemic that affects older adults and causes significant socio-economic burden.Epidemiological data supporting a close relationship between these two aging-related diseases have resulted in the investigation of shared pathophysiological molecular mechanisms.Impaired insulin signaling in the brain has gained increasing attention during the last decade and has been suggested to contribute to the development of Parkinson's disease through the dysregulation of several pathological processes.The contribution of type 2 diabetes mellitus and insulin resistance in neurodegeneration in Parkinson's disease,with emphasis on brain insulin resistance,is extensively discussed in this article and new therapeutic strategies targeting this pathological link are presented and reviewed.
文摘Objective The aims of the present study were to investigate the associations of 46 A〉G, 79 C〉G, 491 C〉T and 659 C〉G genetic variants of the human beta 2-adrenergic receptor (β2-AR), ADRB2, gene with essential hypertension (EH) in Xinjiang Kazakans population.Methods A gender-matched case-control (271 hypertensive cases and 267 normotensive controls) study was used to investigate the associations of the four variations in the coding region of ADRB2 with EH. The genotypes of the variants were identified by the polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP) methods. Results 46 A〉G, 79 C〉G and 659 C〉G polymorphisms were common in the Kazakan population, but 491 C〉T was a mutation (frequency ofT allele was only 0.003) and only found in EH group. The fxequency distributions of genotypes and alleles for 659 C〉G between the EH and control groups was significantly different (P〈0.05), while those for 46 A〉G and 79 C〉G polymorphisms were not statistically different. Logistic regression analysis suggested that the G allele of 659 C〉G polymorphism was a risk factor for hypertension (minor allele vs common homo; odds ratio, 13.240, 95% CI, 4.052-43.274; P〈0.05). Covariance analysis showed that systolic and diastolic blood pressure levels in GG+CG group of 659 C〉G were significantly higher than those in the CC group, but no significant difference of blood pressure were found between common homo and minor allele for 46 A〉G and 79C〉G polymorphisms. Haplotype analysis showed that two hyplotypes, HI: 46A-79C-491C-523C(48%)and H5:46A-79C-491C-659G, were associated with EH.Conelusion ADRB2 genetic variants may play independent roles in the molecular genetic mechanism of EH in Xinjiang Kazakans population (d Geriatr Cardio12010; 7:52-57).
基金This project was carried out under the financial support of USM short-term grant(304/PPSP/6131324)
文摘Aim:In this study,we would like to determine associations between β2-Adrenergic Receptor(β2AR)polymorphisms at codon 16 and 27 and the response to short acting β2-agonist during asthmatic exacerbation.Methods:This was a prospective cross-sectional study of one year duration.One hundred and thirty two asthmatic patients were recruited.Five mls of venous blood was taken for DNA extraction and then genotyped for the β2AR polymorphisms using multiplex PCR.Patient's clinical responses to β2-agonist nebulization were then compared to their genotype to determine the association.Results:We found that there was no association between β2AR polymorphisms at both codon 16 and 27 with response towards short acting β2-agonist,P=0.315 and P=0.706 respectively.Conclusion:We suggested that β2AR polymorphisms at both codon 16 and 27 had no influent on the response to short acting β2-agonist.